The OVERALL OBJECTIVE of this application is to develop a novel quantitative computed tomography (CT)-based method for precise identification of coronary artery lesions that cause ischemia. At present, no non-invasive test exists that determines both coronary artery disease (CAD) stenosis severity and whether a stenosis causes ischemia, or reduced myocardial perfusion. Physiologic stress testing by myocardial perfusion imaging (MPI) is the traditional method for evaluating CAD, and identifies ischemia but not stenoses. In contrast, coronary CT angiography (CCTA) enables direct anatomic visualization of CAD, but cannot discriminate whether a stenosis causes ischemia. By invasive methods, a combined anatomic-physiologic approach to CAD evaluation by invasive coronary angiography and fractional flow reserve (FFR), respectively, improves diagnosis of patients with stenoses that cause ischemia, reduces unnecessary revascularization, and improves clinical outcomes. Recently, a combined anatomic-physiologic approach by non-invasive methods has become possible by the addition of CT perfusion (CTP) to CCTA. Similar to MPI, CTP permits physiologic assessment of stenoses through measures of regional myocardial signal attenuation. Early studies of CTP have been constrained by several limitations, including: 1) shading artifacts; 2) motion artifacts; 3) lack of a quantitative method for assessing perfusion; 4 excess radiation; and 5) an inability to pinpoint specific lesions that cause ischemia. Projection based dual-energy CT (DECT) is a novel CT technology that directly addresses many of these limitations, providing the potential for dramatic reduction in artifacts and quantitative measurement of myocardial perfusion. Coupled with improvements in temporal resolution that reduce motion artifacts, DECT holds the potential to improve the diagnostic accuracy of CTP, with an undoubtedly positive and significant impact on the current diagnostic approach to patients with suspected CAD. The OVERALL HYPOTHESIS of this proposal is that a novel quantitative projection-based DECT-based method will enable discrimination of individuals who suffer from myocardial ischemia as well as the identification of the specific coronary artery lesions that are the cause. For this study, there are 3 specific aims: 1) Develop a novel DECT method that accurately quantifies material density; 2) Determine the in vitro diagnostic accuracy of novel DECT method to characterize myocardial perfusion; 3) Evaluate the in vivo diagnostic accuracy of CTP by the novel DECT method to determine coronary lesion-specific ischemia, as compared to an invasive FFR gold standard.